A major challenge of cancer treatment is to target specific therapies to distinct tumor types in order to maximize efficacy and minimize toxicity. A related challenge lies in the attempt to provide accurate diagnostic, prognostic, and predictive information. At present, tumors are described with the tumor-node-metastasis (TNM) system. This system, which uses the size of the tumor, the presence or absence of tumor in regional lymph nodes, and the presence or absence of distant metastases, to assign a stage to the tumor is described in the American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa.: Lippincott-Raven Publishers, 5th ed., 1997, pp 171-180, and in Harris, J R: “Staging of breast carcinoma” in Harris, J. R., Hellman, S., Henderson, I. C., Kinne D. W. (eds.): Breast Diseases. Philadelphia, Lippincott, 1991. The assigned stage is used as a basis for selection of appropriate therapy and for prognostic purposes. In addition to the TNM parameters, morphologic appearance is used to further classify tumors and thereby aid in selection of appropriate therapy. However, this approach has serious limitations. Tumors with similar histopathologic appearance can exhibit significant variability in terms of clinical course and response to therapy. For example, some tumors are rapidly progressive while others are not. Some tumors respond readily to hormonal therapy or chemotherapy while others are resistant.
Assays for cell surface markers, e.g., using immunohistochemistry, have provided means for dividing certain tumor types into subclasses. For example, one factor considered in prognosis and in treatment decisions for breast cancer is the presence or absence of the estrogen receptor (ER) in tumor samples. ER-positive breast cancers typically respond much more readily to hormonal therapies such as tamoxifen, which acts as an anti-estrogen in breast tissue, than ER-negative tumors. Though useful, these analyses only in part predict the clinical behavior of breast tumors. There is phenotypic diversity present in breast cancers that current diagnostic tools fail to detect. Therefore, there exists a need for improved methods for classifying tumors.
Mutation or dysregulation of any of a large number of genes contributes to the development and progression of cancer as discussed in Hanahan, D. and Weinberg, R., The Hallmarks of Cancer, Cell, 100, 57-70, 2000. Genes that play a role in cancer can be divided into a number of broad classes including oncogenes, tumor suppressor genes, and genes that regulate apoptosis. Oncogenes such as ras typically encode proteins whose activities promote cell growth and/or division, a function that is necessary for normal physiological processes such as development, tissue regeneration, and wound healing. However, inappropriate activity or expression of oncogenes can lead to the uncontrolled cell proliferation that is a feature of cancer. Tumor suppressor genes such as Rb act as negative regulators of cell proliferation. Loss of their activity, e.g., due to mutations or decreased expression at the level of mRNA or protein, can lead to unrestrained cell division. A number of familial cancer syndromes and inherited susceptibility to cancer are believed to be caused by mutations in tumor suppressor genes. Apoptosis, or programmed cell death, plays important roles both in normal development and in surveillance to eliminate cells whose survival may be deleterious to the organism, e.g., cells that have acquired DNA damage. Many chemotherapeutic agents are believed to work by activating the endogenous apoptosis pathway in tumor cells.
Although a substantial number of genes have been implicated as playing important roles in cancer, the factors responsible for the phenotypic diversity of tumors remain largely unknown. In particular, understanding of the underlying differences in gene expression that may contribute to tumor phenotype is limited. Understanding the differences in gene expression between normal and cancerous tissue and between different tumors of the same tissue type is of significant diagnostic, prognostic, and therapeutic utility. There is therefore a need for the identification of genes exhibiting differential expression between tumors. In particular, there is a need for the identification of additional genes and proteins that can be used to classify tumors, especially genes and proteins that can provide diagnostic, prognostic, and/or predictive information in cancer. There is also a need for antibodies and other reagents for the detection and measurement of such genes and proteins.
Most of the commonly used chemotherapeutic agents act relatively nonselectively. Rather than specifically killing tumor cells, these agents target any dividing cell, resulting in a variety of adverse effects. In addition, current therapeutic strategies are of limited efficacy, and the mortality rate of breast cancer remains high. There is therefore a need for the identification of additional genes and proteins that can be used as targets for the treatment of cancer. There is also a need for antibodies and other reagents that can modulate, regulate, or interact with these genes and proteins to provide new method of treatment for cancer.